The Gut Microbiota and Alzheimer’s Disease

Abstract

The gut microbiota comprises a complex community of microorganism species that resides in our gastrointestinal ecosystem and whose alterations influence not only various gut disorders but also central nervous system disorders such as Alzheimer's disease (AD). AD, the most common form of dementia, is a neurodegenerative disorder associated with impaired cognition and cerebral accumulation of amyloid-β peptides (Aβ). Most notably, the microbiota-gut-brain axis is a bidirectional communication system that is not fully understood, but includes neural, immune, endocrine, and metabolic pathways. Studies in germ-free animals and in animals exposed to pathogenic microbial infections, antibiotics, probiotics, or fecal microbiota transplantation suggest a role for the gut microbiota in host cognition or AD-related pathogenesis. The increased permeability of the gut and blood-brain barrier induced by microbiota dysbiosis may mediate or affect AD pathogenesis and other neurodegenerative disorders, especially those associated with aging. In addition, bacteria populating the gut microbiota can secrete large amounts of amyloids and lipopolysaccharides, which might contribute to the modulation of signaling pathways and the production of proinflammatory cytokines associated with the pathogenesis of AD. Moreover, imbalances in the gut microbiota can induce inflammation that is associated with the pathogenesis of obesity, type 2 diabetes mellitus, and AD. The purpose of this review is to summarize and discuss the current findings that may elucidate the role of the gut microbiota in the development of AD. Understanding the underlying mechanisms may provide new insights into novel therapeutic strategies for AD.

Gastrointestinal (GI) Tract Microbes and Microbial Neurotoxins in the Human Central Nervous System (CNS) in Alzheimer’s Disease (AD)

“…recently reported: (i) that RNA sequencing of the V4 region of the 16S rRNA gene in control (n=25) and AD (n=25) patients indicated that sequences representing a total of 4.8 million sequence reads [mean ± one standard deviation (SD) of ~96,000 ± 32,000 reads/participant] were clustered into operational taxonomic units (OTUs; an operational definition used to classify groups of closely related individuals) at 97% similarity [3,5]; (ii) that the final OTU dataset for the control and AD groups consisted of 972 OTUs classified into 95 genera, 46 families, 24 orders, 17 classes and 9 phyla (5); (iii) that there are about ~1000 bacterial species in a typical healthy human GI tract microbiome with a 'GI tract microbial core' of the genus Bacteroides and Firmicutes predominating, and with Proteobacteria, Verrumicrobia, Actinobacteria, Fusobacteria and Cyanobacteria making up the remainder [3,5,6,[12][13][14]; (iv) that at least 13 of 95 microbial genera examined exhibit differential abundance between AD and age-matched control populations [4][5][6]12]; (v) that there are consistent trends observed between relative GI tract bacterial abundance and CSF biomarkers of AD neuropathology [12,15]; (vi) that 16S rRNA next generation sequencing analysis has identified multiple microbial-derived nucleic acids in the AD brain, some of which are known to have pathogenic potential [9]; (vii) that remarkably, the abundance and complexity of microbial populations or their exudates in the GI tract is an approximate reflection of CNS microbial complexity, including microbiome-derived nucleic acid sequences and Gram negative-derived neurotoxins of the GI tract microbiome, such as lipopolysaccharide (LPS; [6,9,[15][16][17][18]); and (viii) that there is a decrease in richness and diversity of GI tract bacteria in AD compared to age-matched controls, a finding that parallels results observed in other GI, vascular or neurological conditions linked to GI tract microbiome alterations, including those associated with obesity, diabetes, inflammatory bowel disease, systemic inflammation and Parkinson's disease [9,[19][20][21][22]. Related to the points above, overall the GI tract microbiome of AD patients was found to exhibit hig...…”

“…Altogether the one thousand or so species of bacteria in the human GI tract might be expected to secrete exceedingly complex mixtures of neurotoxins of many different types and compositions whose actions might exhibit synergism in their neurotoxic potential and abilities to transverse normally protective physiological barriers [1,51,65]. An alternative, yet, highly speculative view is that the human CNS may have its own highly compartmentalized microbiome, which could also explain the presence of abundant bacterial secretory components in the brain as well as multiple forms of microbial-derived nucleic acid sequences [22,50,65,66]. Virtually nothing in known about plant derived microbiomes, plant microRNAs and viroids, natural sncRNAs widely distributed throughout the plant kingdom which are ingested in a regular human diet and how they may contribute to the human microbiome in health and disease [17,65].…”

“…Generally microbial Bacteroidetes species such as Bacteroides fragilis (B. fragilis) appear to be generally beneficial to human health via their ability to cleave dietary fiber into digestible short-chain fatty acids, their production of useful polysaccharides, vitamins and their precursors, volatile fatty acids and other nutrients, however, when they escape the confines of a healthy GI tract microbiome they elicit inflammatory systemic pathology with substantial morbidity and mortality [15,[22][23][24]26]. It is well known that diet has a role in regulating the composition, complexity and speciation of the GI tract microbiome -for example species of Bacteroidetes proliferate in animal models fed high fat-cholesterol (HF-C) diets deprived of dietary fiber [25].…”

“…This agerelated increase in permeability appears to make the normally protected CNS compartments more exposed and potentially susceptible to neurotoxins generated by dietary and/or environmental pathogens and GI tract-resident microbes normally contained within the GI compartment [10,11,62]. Moreover (i) dietary, environmental and pathological infections, including chronic bacterial or viral influences, or disease-related toxins such as LPS, sncRNA and the 42-amino acid amyloid beta (Aβ42) peptide can progressively and permanently alter blood-brain barrier permeability and thereby facilitate cerebral vascular dysfunction and cerebral colonization by opportunistic microbes as we age [11,63]; and (ii) microbial dysbiosis in the GI tract microbiome can induce inflammatory signaling detrimental to both GI tract and BBB dysfunction that is associated with the pathogenesis of obesity, type 2 diabetes and AD [11,22,64]. Indeed, one major contributing factor to AD pathogenesis is cerebral vascular dysfunction due in part to the loss of the protective function of the BBB and impaired clearance of excess neurotoxic Aβ peptides that induce perivascular association with amyloid peptides, vascular perturbation and altered neurovascular function [63,64].…”

“…A commensal genus of non-endospore-forming, rod-shaped bacillus, Bacteroidetes are a human distal-GI-tract-abundant microbe whose membranes contain sphingolipids or glycosylceramides; these complex lipids play important roles in signal transmission and cell recognition and are an unusual feature of obligately anaerobic Gram negative microbes [9,16,22]. Generally microbial Bacteroidetes species such as Bacteroides fragilis (B. fragilis) appear to be generally beneficial to human health via their ability to cleave dietary fiber into digestible short-chain fatty acids, their production of useful polysaccharides, vitamins and their precursors, volatile fatty acids and other nutrients, however, when they escape the confines of a healthy GI tract microbiome they elicit inflammatory systemic pathology with substantial morbidity and mortality [15,[22][23][24]26].…”